Derivatives of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine and process for making same

ABSTRACT

The present invention concerns novel therapeutic compounds having the formula: ##STR1## wherein R is a basic compound comprising 2-amino-4-methylpyridine or 2-amino-2-thiazoline, and methods of making this compound.

This is a division of application Ser. No. 448,748 filed Mar. 6, 1974, now U.S. Pat. No. 3,994,910.

BACKGROUND OF THE INVENTION

Since its discovery almost a quarter of a century ago, phenylbutazone (4-n-butyl-1,2-diphenyl-3,5-pyrazolidinedione) has dominated the field of non-steroid anti-inflammatory drugs despite the fact that it has several serious toxic effects of which ulcerogenesis and fluid retention are probably the most frequent.

The most probable reason for the continued success of phenylbutazone is that none of the numerous modifications of its structure nor the even more numerous attempts to design novel structures with anti-inflammatory activity have resulted in a truly successful separation of desired pharmacological activity and undesired toxicity.

SUMMARY OF THE INVENTION

This invention relates to a process for preparing derivatives of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine having the formula: ##STR2## in which R is represented by a basic compound namely: either 2-amino-4-methyl-pyridine or 2-amino-2-thiazoline, having the respective formulae: ##STR3##

It has been found that the compounds of Formula I are a clear improvement over phenylbutazone in that they have increased therapeutic activities but reduced or decreased toxicity.

As will be more fully discussed hereinafter, the therapeutic compounds of the present invention have a number of additional advantages over phenylbutazone. For example, smaller doses of the new therapeutic compounds as compared with phenylbutazone can be used with comparable and superior effectiveness. The therapeutic compounds of the present invention have fewer and less severe side effects.

In equimolar reaction with 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine, these compounds form stable crystalline combinations with an interesting therapeutic action as antiinflammatories, analgesics and analeptics.

Pharmacological testing of these compounds led to results to be described hereinafter and reflected in the compound formed by the equimolar combination of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine-2-amino-2-thiazoline, referred to hereinafter as LAS-11871. The equimolar combination of phenylbutazone salt with 2-amino-4-methylpyridine is hereinafter referred to as LAS 6671.

The doses of compounds referred to are in mg of salt and not in mg equivalents of phenylbutazone content (i.e., the comparison has been made on a weight for weight basis and not equimolar) since it was considered that this would be more demonstrative of the potential value of the compound. Equimolar comparisons can be made by taking into account the respective molecular weights of LAS 11871 (410.54) and phenylbutazone (308.4) from which it is evident that 100 mg. of LAS 11871 contains the equivalent of 75 mg of phenylbutazone.

DETAILED DESCRIPTION OF THE INVENTION

The properties and advantages of the therapeutic compounds of the present invention will be discussed below as to some of their therapeutic activities, their toxicity effects and their chemical functions and synthesis.

PHARMACOLOGY

LAS 11871 and 6671 were compared in a preliminary screening test with phenylbutazone and a commercially available piperazine salt of phenylbutazone and they had definite advantages over each of these two products (see Table I below).

TABLE I

This shows the effects of LAS- 11871 in various screening tests as compared with phenylbutazone and a piperazine salt thereof.

    ______________________________________                                                    Desired Effects                                                                              Toxic Effects                                         Compound     CE      AA      AP    UG    TX                                    ______________________________________                                         LAS 11871    ++      +++     +++   ++    +                                     LAS 6671     ++      +       ++    ++    +                                     Phenylbutazone                                                                              ++      ++      ++    ++    ++                                    Piperazine salt                                                                of Phenylbutazone                                                                           +       +       +     +     +                                     ______________________________________                                          CE = Inhibition of carrageenin-induced oedema in rat's paw.                    AA = Inhibition of contortions induced by acetic acid in mice.                 AP = Inhibition of yeast-induced pyrexia in rats.                              UG = Intensity of ulceration produced in the rat stomach.                      TX = Acute toxicity in mice.                                             

More detailed studies confirmed these preliminary results and clearly showed that LAS 11871, although more active as an analgesic and anti-inflammatory agent than phenylbutazone, produces fewer gastric lesions and is less toxic than phenylbutazone (see Tables 2, 3, 4, 5 and 6 below).

TABLE 2

This shows the effect of various doses of phenylbutazone and LAS 11871 on carrageenin-induced oedema in the rat's paw.

    ______________________________________                                         Compound per os     Volume of paw % Inhibition                                 1 h before  No. of  (ml) standard ± standard                                carrageenin animals error         error                                        ______________________________________                                         Control     46      0.9663 ± 0.0564                                                                            0.00 ± 5.80                              Phenylbutazone 200                                                                         12      0.2458 ± 0.0454**                                                                         74.60 ± 4.70                              100         18      0.3139 ± 0.0224**                                                                         67.50 ± 2.30                               50         22      0.6886 ± 0.0699*                                                                          28.70 ± 7.24                               25         22      0.6545 ± 0.0545**                                       LAS 11871 200                                                                              11      0.1545 ± 0.0384**                                                                         84.00 ± 3.97                              100         18      0.2667 ± 0.0428**                                                                         72.40 ± 4.43                               50         22      0.6182 ± 0.0683*                                                                          36.01 ± 7.06                               25         22      0.7864 ± 0.0632                                                                           18.60 ± 6.54                              ______________________________________                                    

Volume of paws measured 3 hours after injection of carrageenin *P <0.05, >0.001; **P <0.001 for the differences from the control using Student's "t" test.

                                      TABLE 3                                      __________________________________________________________________________     Effects of various doses of phenyl butazone and LAS 11871                      on granuloma induced in rats by implantation of cotton balls.                  __________________________________________________________________________                                          Percentage                                             No. of         Dry granuloma ±                                                                      inhibition                                mg/Kg/day of compound                                                                       granulomas                                                                           Weight of wet                                                                          standard error                                                                           Wet    Dry                                per os       (animals)                                                                            granuloma                                                                                 (mg)   granuloma                                                                             granuloma                          __________________________________________________________________________     Control      40 (20)                                                                              454.20 ± 11.74                                                                       77.34 ± 0.33                                                                          0.00 ± 2.60                                                                        0.00 ± 0.40                    Phenylbutazone 200                                                                          20 (10)                                                                              353.40 ± 13.14**                                                                     49.96 ± 4.25**                                                                       22.20 ± 2.80                                                                       35.40 ± 5.50                    100          20 (10)                                                                              424.50 ± 13.47                                                                       71.23 ± 5.18                                                                          6.50 ± 2.90                                                                        7.90 ± 6.70                     50          20 (10)                                                                              434.75 ± 18.36                                                                       83.94 ± 8.22                                                                          4.30 ± 4.10                                                                        8.50 ± 10.6                    LAS 11871 200                                                                               20 (10)                                                                              361.21 ± 12.84**                                                                     48.29 ± 1.98**                                                                       20.50 ± 2.80                                                                       37.60 ± 2.50                    100          20 (10)                                                                              369.69 ± 16.68**                                                                     61.95 ± 4.74*                                                                        18.60 ± 3.70                                                                       19.90 ± 6.10                     50          20 (10)                                                                              388.59 ±  8.74**                                                                     61.82 ± 3.16**                                                                       14.40 ± 1.90                                                                       20.00 ± 4.10                    __________________________________________________________________________      The figures refer to the net weight of granuloma tissue obtained by            subtracting the original weight of the cotton ball.                            *P <0.05, >0.001                                                               **P <0.001 for the differences from the control using Student's "t" test.

                  TABLE 4                                                          ______________________________________                                         Effect of various doses of phenylbutazone and LAS 11871                        on cortortions induced by acetic acid                                          injected into the abdominal cavity of the mouse                                ______________________________________                                         mg/kg of compound    No. of                                                    per os 1 h before                                                                          No. of   contortions ±                                                                           % inhibition ±                             acetic acid injection                                                                      animals  standard error                                                                             standard error                                ______________________________________                                         Control     20       81.65 ± 5.73                                                                             0.00 ± 7.02                               Phenylbutazone 300                                                                         10       42.30 ± 6.75**                                                                          48.20 ± 8.27                               100         10       47.30 ± 6.70*                                                                           42.10 ± 8.20                                30         10       59.00 ± 6.51*                                                                           27.70 ± 7.97                               LAS 11871 300                                                                              10       24.10 ± 3.74**                                                                          70.50 ± 4.60                               100         10       36.90 ± 6.34**                                                                          54.90 ± 7.76                                30         10       44.20 ± 6.03**                                                                          45.90 ± 7.39                               ______________________________________                                          *P <0.05, >0.001                                                               **P >0.001 for the differences from the control using Student's "t" test.

TABLE 5

Ulcerogenic activity of LAS 11871 on the stomach as compared with phenylbutazone

                  TABLE 5                                                          ______________________________________                                         Ulcerogenic activity of LAS 11871 on the stomach as compared                   with phenylbutazone                                                            ______________________________________                                         mg/kg of compound                                                                             No. of    ± standard error of                                per os         animals   ulcerogenic indices                                   ______________________________________                                         Control        40        0.17 ± 0.07                                        Phenylbutazone 2×200                                                                    29        5.00 ± 0.56                                        2×100    30        4.33 ± 0.47                                        2× 50    30        0.73 ± 0.21                                        LAS 2×200                                                                               29        3.65 ± 0.56*                                       2×100    30        2.43 ± 0.41**                                      2× 50    29        0.59 ± 0.19                                        ______________________________________                                          *P <0.1, >0.01                                                                 **P <0.01 for the differences between equivalent doses of phenylbutazone       and LAS 11871 using Student's "t" test.                                  

From Table 2 it is demonstrated that LAS 11871 is at least as active as phenylbutazone against inflammation and at doses of 50 mg/kg and above LAS 11871 was the more active compound.

Table 3 compares the activity of LAS 11871 and phenylbutazone against chronic inflammation. It is seen that although both products produced about the same degree of inhibition of granuloma tissue formation at high doses (200 mg/kg), at the lower dose levels (100 and 50 mg/kg) LAS 11871 continued to inhibit the granuloma tissue formation but phenylbutazone did not.

Table 4 demonstrates that LAS 11871 is more potent than phenylbutazone as an analgesic.

Although LAS 11871, in common with virtually all of the other non-steroid anti-inflammatory compounds, possesses a certain capacity to cause ulcerous lesions in the gastro-intestinal tract. However, as Table 5 illustrates, it is much less active in this respect than phenylbutazone.

    ______________________________________                                         TOXICITY                                                                       LD50 per os in the rat of LAS 11871                                            Group Dose       No. animals                                                                               No. deaths                                                                             % mortality                                ______________________________________                                         I     1000 mg/kg 10         1       10                                         II    1210 mg/kg 12         3       25                                         III   1470 mg/kg 10         5       50                                         IV    1780 mg/kg 10         9       90                                         V     2150 mg/kg 10         10      100                                        LD50 = 1425 mg/kg (1250 - 1624)                                                LD50 per os in the rat of phenylbutazone                                       Group Dose       No. animals                                                                               No. deaths                                                                             % mortality                                ______________________________________                                         I      464 mg/kg  9         1       11                                         II     562 mg/kg 10         4       40                                         III    681 mg/kg 10         8       80                                         IV     825 mg/kg 10         8       80                                         V     1000 mg/kg 10         9       90                                         VI    1210 mg/kg 10         10      100                                        LD50 = 620 (530 - 725)                                                         LD50 per os in the rat of 2-amino-thiazoline                                   Group Dose       No. animals                                                                               No. deaths                                                                             % mortality                                ______________________________________                                         I     316 mg/kg  10         2       20                                         II    383 mg/kg  10         4       40                                         III   464 mg/kg  10         6       60                                         IV    562 mg/kg  10         7       70                                         V     681 mg/kg  10         9       90                                         VI    825 mg/kg  10         9       90                                         LD50 = 430 mg/kg (358 - 516)                                                   ______________________________________                                    

In general, the new therapeutic compounds can be used to treat the same disorders as phenylbutazone. As the above discussion illustrates, the therapeutic compounds of the present invention are less toxic and less ulcerogenic than phenylbutazone, and they have greater effectiveness in anti-inflammatory, analgesic, and antipyretic activity. These therapeutic compounds have been found effective in treating humans as well as animals. For example, LAS 11871 has been shown effective in the treatment of humans with reumatic diseases and LAS 11871 has been used to successfully treat polyarthritics at doses of 200 mg. two, or three times per day.

These new therapeutic compounds also have limited and reduced side effects. As noted earlier, they have no anti-diuretic effect and relatively low ulcerogenic potential. They are also relatively free of serious side effects on the central nervous system.

However, the compounds, much more than phenylbutazone, show marked inhibition of spontaneous motor activity. This activity is best described as a tranquilizing or muscle relaxant activity. Also, the compounds appear to have immunosuppressant activity.

    ______________________________________                                         PHARMACEUTICAL FORMULATIONS -                                                   LAS 11871 capsules     g                                                      ______________________________________                                         LAS 11871               0.200                                                  Colloidal silica        0.005                                                  LAS 11871 tablets                                                              LAS 11871               0.250                                                  Hydroxypropyl cellulose 0.016                                                  Microcrystalline cellulose                                                                             0.100                                                  Carboxymethyl starch    0.012                                                  Colloidal silica        0.003                                                  Magnesium stearate      0.003                                                  LAS 11871 suppositories                                                        LAS 11871               0.300                                                  Stearine composition    1.240                                                  LAS 11871 suppositories                                                        LAS 11871               0.5000                                                 Ascorbyl palmitate      0.0025                                                 Stearine composition    1.9975                                                 Dose: from 200 to 1,500 mg/day                                                 ______________________________________                                    

CHEMISTRY AND SYNTHESIS

The reaction process for synthesising the therapeutic compounds of the present invention is carried into effect with the use of organic solvents such as methanol, ethanol, acetone, methyl ethyl acetone and dioxane in conditions which will be described in the following Examples.

EXAMPLE 1 Equimolar combination of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine-2-amino-4-methyl-pyridine.

30.8 g (0.1 mol) of 1,2-diphenyl-3,5-dioxo-4-butyl-pyrazolidine are introduced with agitation into a 500 cc flask and mixed with 150 ml of acetone until complete dissolution. 10.8 g (0.1 mol) of 2-amino-4-methylpyridine which have previously been dissolved in 100 cc of acetone are then added and the mixture is boiled for 30 minutes. It is filtered cold, and 39 g of a product having a melting point of 121°-2° C are crystallized out.

EXAMPLE 2 Equimolar combination of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine-2-amino-2-thiazoline.

Working is performed under the same conditions as in Example 1 but using ethyl alcohol as the solvent. 2.04 g (0.02 mol) of 2-amino-2-thiazoline are heated in ethanol with 6.16 g (0.02 mol) of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine for 30 minutes; after cooling, the crystals which form are collected. The substance has a melting point of 161°-2° C. The yield is 86%. The final product was a white crystalline powder virtually insoluble in ether, sparingly soluble in water and soluble in hot ethanol. 

What is claimed is:
 1. A pharmaceutical composition having anti-inflammatory activity in humans as well as in other animals, said composition comprising a therapeutic compound having the formula: ##STR4## in which R is 2-amino-2-thiazoline having the formula: ##STR5## together with a non-toxic pharmaceutically acceptable carrier or diluent therefor, said therapeutic compound present in sufficient amount to exhibit said activity.
 2. The composition of claim 1 wherein said composition contains a dose of the therapeutic compound in the range 50-250 mg.
 3. The composition of claim 1 wherein the composition is formulated so as to provide the equivalent of 200-1,500 mg/day of said therapeutic compound to the host.
 4. The composition of claim 1 wherein it is in the form of a capsule.
 5. The composition of claim 1 wherein it is in the form of a suppository.
 6. The composition of claim 1 wherein it is in the form of a tablet.
 7. A pharmaceutical composition having analgesic activity in humans as well as in other animals, said composition comprising a therapeutic compound having the formula: ##STR6## in which R is 2-amino-2-thiazoline having the formula: ##STR7## together with a non-toxic pharmaceutically acceptable carrier or diluent therefor, said therapeutic compound present in sufficient amount to exhibit said activity.
 8. The composition of claim 7 wherein said composition contains a dose of the therapeutic compound in the range 50-250 mg.
 9. The composition of claim 7 wherein the composition is formulated so as to provide the equivalent of 200-1,500 mg/day of said therapeutic compound to the host.
 10. The composition of claim 7 wherein it is in the form of a capsule.
 11. The composition of claim 7 wherein it is in the form of a suppository.
 12. The composition of claim 7 wherein it is in the form of a tablet.
 13. A pharmaceutical composition having anti-pyretic activity in humans as well as in other animals, said composition comprising a therapeutic compound having the formula: ##STR8## in which R is 2-amino-2-thiazoline having the formula: ##STR9## together with a non-toxic pharmaceutically acceptable carrier or diluent therefor, said therapeutic compound present in sufficient amount to exhibit said activity.
 14. The composition of claim 13 wherein said composition contains a dose of the therapeutic compound in the range 50-250 mg.
 15. The composition of claim 13 wherein the composition is formulated so as to provide the equivalent of 200-1,500 mg/day of said therapeutic compound to the host.
 16. The composition of claim 13 wherein it is in the form of a capsule.
 17. The composition of claim 13 wherein it is in the form of a suppository.
 18. The composition of claim 13 wherein it is in the form of a tablet.
 19. A pharmaceutical composition for treating rheumatic diseases in humans as well as in other animals, said composition comprising a therapeutic compound having the formula: ##STR10## in which R is 2-amino-2-thiazoline having the formula: ##STR11## together with a non-toxic pharmaceutically acceptable carrier or diluent therefor, said therapeutic compound present in an effective amount for carrying out said treatment.
 20. The composition of claim 19 wherein said composition contains a dose of the therapeutic compound in the range 50-250 mg.
 21. The composition of claim 19 wherein the composition is formulated so as to provide the equivalent of 200-1,500 mg/day of said therapeutic compound to the host.
 22. The composition of claim 19 wherein it is in the form of a capsule.
 23. The composition of claim 19 wherein it is in the form of a suppository.
 24. The composition of claim 19 wherein it is in the form of a tablet. 